One of the primary objectives of the work in this laboratory is to further our understanding of the site and mechanism of action of antipsychotic drugs. Previously we have found, using intracellular single unit recording and microiontophoretic techniques, that repeated treatment with haloperidol (0.5 mg/kg/day, s.c. x 22 days) induces an almost complete cessation of dopaminergic neuron activity in the substantia nigra zona compacta. Further studies, using indirect methods, have suggested that this inactivity of dopamine cells is due to their development of apparent tonic depolorization block which is mediated via striatonigral feedback pathways. In order to begin to understand how repeated treatment with haloperidol could induce such an effect we are carrying out basic neurophysiological and neuroanatomical studies to gain further information about the way dopamine cells fire and the various ways that their activity is regulated. We have found that peripheral stimuli, such as toe pinch or stimulation of the sciatic nerve, induce an initial inhibition of dopamine cell activity in untreated animals which is followed by an oscillating pattern of excitation and inhibition which damps out over time. Lesion of the striato-nigral feedback pathways prevents this oscillation suggesting that we have a model system which will allow us to study neuronal feedback regulation of dopamine cell activity and the effects of drugs upon it. We have also developed in vivo intracellular recording from neurochemically identified nigral dopaminergic neurons. Using this technique we will attempt to characterize the neurophysiological mechanisms (at a membrane level) involved in: (1) the normal activity of dopaminergic neurons, (2) changes in their activity induced by a variety of dopamine agonists and antagonists administered both acutely and chronically. Other studies are in progress which are designed to examine the effects of a cholecystokinin-like peptide on dopamine cell activity as well as modulation of dopamine cell activity by noradrenergic and serotonergic neurons.